One can observe that the structure of Baccatin III (2) ##STR2## has the basic diterpenoid structure of taxol without the side chain at the C-13 position. Thus, Baccatin III and the other related Baccatins are important starting materials in taxol semi-synthesis. The significance of Baccatin III may increase as more taxol cancer testing is performed. Already it appears that water soluble taxol-like compounds with slightly modified C-13 side chains may be more desirable as cancer drugs than the natural occurring less soluble taxol. This increases the unresolved need for Baccatin III as a starting material to synthesize taxol and second and third generation taxol-like compounds.
The present source of Baccatin III is extraction from the English Yew (Taxus Baccatta). The supply of this raw material is limited. Conversion of taxol and cephalomannine into Baccatin III is a viable method of increasing the supply of Baccatin III.
Miller reported that cephalomannine was converted in a 19% yield to Baccatin III by methanolysis in the presence of sodium bicarbonate. See, Journal of Organic Chemistry, Volume 46, pp. 1469-1474 (1984). Preparation of a 97% yield of Baccatin III from pure taxol was reported by Magris, et al. See, "Modified taxols, 3. Preparation and Acylation of Baccatin III", Journal of Organic Chemistry, Vol. 51, pp. 3239-3242, 1986. The preparation of Baccatin III according to the Magris, et al process was performed as follows: a 100 mg sample of pure taxol in dry CH.sub.2 CL.sub.2 (2.0 mL) was allowed to react with Bu.sub.4 NBH.sub.4 (50 mg) for one hour, and the reaction was quenched with 0.5 mL of AcOH. The mixture was stirred ten minutes, evaporated, and the product isolated by preparative TLC. This process was reported to give a 97% yield of Baccatin III from pure taxol.
The Magris, et al paper also indicated that this reaction was run on a starting material consisting of an unpurified taxol/cephalomannine mixture and the result was a reduced yield of Baccatin III compared to using pure taxol as the starting material. High yield conversion of pure taxol to Baccatin III is extremely useful in the laboratory where pure taxol is available. However, there is a need for a high yield process to convert crude taxane mixtures (containing taxol/cephalomannine and other taxanes) into Baccatin III.
In the commercial extraction of taxol from yew tree material, significant quantities of taxanes including taxol and cephalomannine are generated These mixtures contain useful taxanes (which are thrown away as by-products in the purification of taxol). The Magris, et al process has not demonstrated particularly high yield results when partially purified mixtures containing low percentages of taxol and cephalomannine are converted into Baccatin III.
In large scale processing of taxol for commercial use, the cost associated with achieving the Magris, et al yield is not economically feasible. The Magris, et al process uses tetrabutylammonium borohydride, an expensive reducing salt. Furthermore, this procedure is run at 0.degree. C. which adds refrigeration costs to the final product. Most taxane extraction processes result in by-products containing some taxol, cephalomannine and significant amounts of other substances. Therefore, there remains a need for a high yield inexpensive process of converting these partially purified mixtures of taxanes including taxol and/or cephalomannine into Baccatin III.